A method of introducing (delivering) ionic drug (ionic chemical substance) placed at a desired part of the skin or mucosa (hereinafter simply called the skin) into the body through the skin by giving the skin an electromotive force sufficient to drive such ionic drug is called iontophoresis (ion introduction method or ion delivery treatment) (See, for example, JP-A-63035266 for the above-mentioned definition of iontophoresis).
As described above, iontophoresis performs desired medical treatment by driving (carrying) an ionizable or ionic drug, which has been applied on the skin, under predetermined electromotive force to deliver the same into the skin.
For example, positively charged ions are driven (carried) into the skin on the side of an anode in an electric system of an iontophoresis device.
Negatively charged ions, on the other hand, are driven (carried) into the skin on the side of a cathode in the electric system of the iontophoresis device.
The following are examples of ionic drugs to which the above-described iontophoresis is applicable.
(1) Positively Chargeable Ionic Drugs:
Local anesthetic drugs (procaine hydrochloride, lidocaine hydrochloride, etc.), gastrointestinal drugs (calnitine chloride, etc.), skeletal muscle relaxants (pancuronium bromide, etc.), and antibiotics (tetracycline derivatives, kanamycin derivatives, gentamicin derivatives).
(2) Negatively Chargeable Ionic Drugs:
Vitamins (hereinafter abbreviated as V) (VB2, VB12, VC, VE, folic acid, etc.), adrenocorticosteroids (hydrocortisone water soluble drugs, dexamethazone water soluble drugs, prednisolone water soluble drugs, etc.), and antibiotics (penicillins water soluble drugs, chloramphenicol water soluble drugs).
Concerning methods for administering ionic drugs by iontophoresis and devices to be used in the practice of such methods, research and development have been made for many years, and a variety of methods and devices have been proposed.
Conventional art on this type of iontophoresis includes those using ion exchange membranes. The present invention also belongs to the category of technology using ion exchange membranes as will be described in detail below.
To facilitate understanding of the present invention that makes use of ion exchange membranes, a detailed description of typical examples of the prior art using ion exchange membranes will be given below.
1. Japanese Language Laid-open Publication (PCT) No. HEI 3-504343 (International Publication No. WO90/04433), International Publication Date: May 3, 1990 (Hereinafter Called the Prior Art 1):
                (1) The prior art 1 discloses an iontophoresis electrode, comprising (i) an electrode plate, (ii) a reservoir for storing an ionic (or ionizable) drug to be delivered, and (iii) an ion exchange membrane disposed on an outer side (skin-contacting side) of the reservoir and selective to ions charged in the same polarity as the ionic drug.        (2) In the prior art 1, the function of the ion exchange membrane is described that, in the process of carrying (driving) the ionic drug toward the skin, the ion exchange membrane restricts movement of ions which are charged electrically opposite to the ionic drug and move from the skin toward the electrode plate. For example, it inhibits movement of ion species existing on the skin such as sodium ions, chlorine ions and other ions which may form an ionic current path different from the current path formed by the ionic drug.        
(3) The prior art 1 also describes that the efficiency of administration of the ionic drug is increased because the ion exchange membrane reduces migration of other mobile charge carriers into the reservoir containing the ionic drug.
2. U.S. Pat. No. 4,722,726 (Hereinafter Called the Prior Art 2):
(1) The prior art 2 is referred to as a related art in the patent specification of the prior art 1, and discloses an electrode of the following construction:
(i) the electrode is divided into a first chamber containing an electrolyte and a second chamber containing an ionized ingredient, and
(ii) the first chamber and the second chamber are isolated from each other by an ion exchange membrane.
(2) The prior art 2 describes that the first chamber containing the electrolyte can lessen the deleterious effects of hydrolysis of water and that the ion exchange membrane can isolate the ionic drug from the electrolyte in the first chamber.
However, the technology disclosed in the prior art 2, which uses electrolyte, also has an undesirable facet that the efficiency of transport (transference number) of charged ions of the active ingredient in the ionic drug is apparently lowered, because it increases the concentration of other additional ion species in the system.
Therefore, care should be taken in adopting a technology which uses electrolyte in this way.
3. JP-A-03094771 (Hereinafter Called the Prior Art 3):
(1) The prior art 3 discloses an electrode for iontophoresis comprising (i) a water retaining portion surrounded by a flexible supporting member and having an electrode plate inside, (ii) an ion exchange membrane disposed on a front side (skin side) of the water-retaining portion, and (iii) a drug layer (ionic drug layer) disposed on a front side (skin side) of the ion exchange membrane.
(2) The prior art 3 is intended to administer an ionic drug of a high concentration while preventing dilution of the drug with water in the course of administration of the drug.
(3) For this purpose, the prior art 3 discloses an iontophoresis electrode having an ion exchange membrane which substantially inhibits permeation of the drug but is water-permeable and a drug layer formed on the body (skin) contacting side of the ion exchange membrane by adhering or depositing the drug by such methods as spray drying and spreading.
4. JP-A-04297277 (Hereinafter Called the Prior Art 4):
(1) The prior art 4 relates to the preceding Japanese patent application filed by this applicant. In FIG. 2, for example, the prior art 4 discloses an iontophoresis electrode section (active electrode section) (in FIG. 2, the negative electrode functions as an active electrode section in relation to the polarity of ions of an ionic drug to be employed) constructed in a multilayer structure of negative electrode plate/gauze with the ionic drug contained therein/cation exchange membrane/gauze with the ionic drug contained therein/anion exchange membrane.
(2) The iontophoresis technology disclosed in the prior art 4 is the technology which has been improved by the present invention, and the limitations of the prior art 4 will be discussed in detail when the present invention is described below.
As to the number of the ion exchange membrane(s) used (arranged) in the iontophoresis electrode section (active electrode section) in each prior art described above, the prior arts 1 through 3 disclose a single layer structure using a single ion exchange membrane, while the prior art 4 discloses a double layer structure using two ion exchange membranes. In this respect, the prior art 4 is different from the other prior arts 1 through 3.
The present invention as will be described in detail below uses a double layer structure like the prior art 4. However, the present invention is based on a technical concept totally different from prior art 4, as it has distinct features that one or more ion exchange membranes are also arranged in the ground electrode section that ion exchange membranes are arranged as many as three or four in total in the iontophoresis device, and, moreover, that both electrode sections have been reconstructed so as to keep the transference number of charged drug ions at a high level and significantly improve the ease (convenience) of handling.
As described above, use of ion exchange membrane(s) has been known in transdermal administration of an ionic drug by iontophoresis.
The above-described conventional iontophoresis technologies using one or more ion exchange membranes, however, lacked a concept or idea of preventing or eliminating various drawbacks associated with an electrochemical reaction on a surface of an electrode plate in the iontophoresis electrode section (active electrode section) and/or the ground electrode section (inactive electrode section).
In other words, the conventional iontophoresis technologies using ion exchange membrane(s) lacked the concept of paying attention to all electrochemical reactions at an iontophoresis electrode section (active electrode) and a ground electrode section (inactive electrode section) and of eliminating drawbacks caused by such reactions in order to establish an iontophoresis technology of higher added value.
In the conventional iontophoresis technologies using ion exchange membrane(s), more specifically, those of the above-described prior arts, one or more ion exchange membranes are used in an active electrode section but no ion exchange membrane is employed in an inactive electrode section, and consequently they have the following drawbacks:
(i) It is difficult to administer an ionic drug (to perform drug delivery) for a long period of time under stably energized conditions (it is difficult to keep it operating for a long period of time at a constant voltage or constant current). For example, physiological saline which is an electrolyte solution (a solution containing an electrolyte substance) is hydrolyzed to produce gas bubbles (oxygen gas, chlorine gas, etc.) on a surface of an electrode plate in an active electrode section of positive (+) polarity, although the polarity of the active electrode section differs depending upon the polarity of charged ions of an active ingredient in an ionic drug. Due to such gas bubbles, the electric resistance increases, resulting in a substantial reduction in the iontophoresis effect (the efficiency of transport of ions) with time. This reduction also takes place by gas bubbles (hydrogen gas and the like) produced at the ground electrode section of negative (−) polarity.
(ii) Burn, inflammation or the like (including electrical burn caused by a current itself or pH-induced burn caused by a sudden change in pH due to H+ or OH− produced by electrolysis) may occur on the skin at its surface which is in contact with the active electrode section and/or the ground electrode section.
(iii) The skin may be damaged at its surface, which is in contact with an electrode plate [for example□positive(+)□electrode] in the active electrode section, by a harmful substance formed through hydrolysis of sweat on the skin surface and/or physiological saline as an electrolyte solution, for example, by hypochlorous acid (which is known as a strong oxidizing agent) produced based on Cl− (chlorine ions) and as a result of high acidification (production of HCl).
(iv) The skin may be damaged at its surface, which is in contact with an electrode plate [for example, negative (−) electrode] in the ground electrode section, by a harmful substance formed through hydrolysis of sweat on the skin surface and/or physiological saline as an electrolyte solution, for example, as a result of high alkalinization (production of NaOH).